Diseases of the CNS are associated with alterations in blood-brain barrier (BBB) permeability which may be related to disturbances of adrenergic input. This research examined the mechanism(s) involved in the expression of adhesion molecules on brain endothelial cells (EC). One of the mechanisms by which immunologically competent inflammatory cells gain access to the brain is via cytokine-induced expression of adhesion molecules on EC. Initial projects explored the effect of adrenergic agents on the expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor-alpha (TNF-alpha). The in vitro model system consisted of <95% pure cerebral microvascular EC derived from human brain (HBMEC). ICAM-1 expression on cultured HBMEC was assesed by FACS analysis and quantitated by ELISA; cAMP was assayed by RIA. Monolayers of HBMEC were incubated with various concentrations (1-20 uM) of isoproterenol alone or in the presence of propanolol (10 uM). HBMEC were incubated for 30 min followed by the addition of 10-200 U/ml TNF-alpha. Early time course experiments demonstrated expression at 4-6 h with a maximal expression seen at 24-48 h. TNF-alpha dose-dependently up-regulated ICAM-1 expression on HBMEC. Concomitant treatment with isopreterenol dose-dependently down-regulated the TNF-alpha induced expression of ICAM-1. This observation indicated that adrenergic agents might be involved in ICAM-1 expression at the site of the BBB. Propanolol (a1/a2-adrenergic antagonists) and butoxamine (B2-adrenergic antagonist), but not atenolol (B- adrenergic antagonist) reversed the inhibitory effect induced by isoproterenol. In addition to quantitative ICAM-1 expression, we investigated the mechanism by which isoproterenol modulated the TNF-alpha-induced ICAM-1 expression. Isoproterenol dose-dependently stimulated cAMP production by HBMEC. Elevated levels of cAMP were also seen in the presence of TNF-alpha. Treatment of HBMEC with propanolol abolished this effect. These findings indicated that the B2-adrenergic receptor/cAMP pathway may be partly involved with TNF-alpha-stimulated ICAM-1 expression. The results support the adrenergic involvement in capillary function and BBB integrity. Further studies will examine the existence of similar mechanisms in the expression of adhesion molecules in hypoxia/ischemia. This may provide a better understanding of the involvement of BBB in pathological conditions such as stroke and may yield novel possibilities for therapeutic intervention.